Reversing silenced AR signal with demethylating agents - A promising treatment option?

[boston332]

Shippen said “a doctor in Europe” was having success with procaine. So, not sure if he was talking about Awor or someone else. Shippen has spoken to this doctor.

According to them I can inject this at 1 cc daily. If I dont feel anything in a week I go up to 2 cc’s and so on. I’m going to put a small maintenance amount of b12 in the same syringe when I do the injections.

[191]

I would pm awor and see what he thinks and whether he is that person.

[boston332]

Yes, I have PM’ed Awor to get his thoughts. I have not heard back yet. He hasn’t been very active on the forum lately. Hopefully his treatment is still going well.

I got the impression from Dr. Shippen that the results from whomever he was talking about in Europe are very promising however its very early stages and much is yet to be learned.

Will be very interesting if this “works” on two of us…

[191]

I am certainly considering it but not sure where to have it done.

[Bradwaggoner]

Is there some evidence that finasteride causes an over-methylation either directly or indirectly? Just interested in how this theory came about.

[boston332]

Theory came about to neatly explain why we don’t respond to androgens, sometimes supraphysiologic amounts. At this point it is all educated guessing until a research epigenetic scientist performs a study. True “evidence” would only be found this way. This would take alot of time and money. But, most of the PFS docs I have spoken with (four of them) feel this is the issue. And, Awors positive results, even though very early on, seem to bolster the theory. Hopefully I will be starting this on Wednesday. Two of us improve on this we are onto something. Should know soon.

Awor has recieved my message but has not responded yet. I’m sure he’s getting a ton of PM’s though. Would be interested to know if he thinks injections will be effective as IV administration considering the half life of the drug.

[Bradwaggoner]

Well keep us posted man. Very interesting.

[Oscar]

@awor

Having been on TRT before taking fin, I know what even small doses of TRT normally feels like: Good. Now, no matter what I take, I feel nothing positive - actually high doses of androgens make my symptoms WORSE. I’ve also messed with reducing estrogens via Arimidex and even Aromasin. Nada.

For those that have been there, the conclusion is clear: Androgen insensitivity is the only answer. There is no way on this frickin planet that any hormonal “excuses” can even come close to explaining this. If you think about it, what has happened becomes very clear:

5AR inhibitor massively reduces cellular and circulating DHT levels
AR becomes hypersensitive (google terms androgen receptor hypersensitivity) due to low androgens. This is why we get hypogonadal LH/T values.
Side effects start
We quit 5AR inhibitor
DHT returns full force and hits upon hypersensitive AR (do the math 100% > 30% is a 70% reduction. 30% to 100% is a 333% increase. Combine this with a hypersensitive AR and you get a train crash. This is why the symptoms really go south about 1-2 weeks after quitting.
AR negative autoregulation kicks in an probably methylates some AR regulatory element, effectively silencing the AR signlal

The approach we have to take to this is to understand what changed and try to undo it. Overloading the system with further hormones will not work in many cases. Some guys do indeed seem to be lucky enough to have enough remaining sensitivity to get some benefit from hormones. Most of us, however will not - or even get worse by using them.

Btw, common misconception on this board: Adiol-G is about 75% a marker of AR gene expression and NOT of 5AR activity. 3a-HSD is mainly induced by AR gene expression. The remaining 25% come from direct induction by androgens (likely) or some other hormone (maybe). That is why you can have perfectly good serum DHT values and still have fucked up Adiol-G, because low Adiol-G is mostly telling us something about Androgen sensitivity.

@possibly awor

There currently is no proof that 5AR2 deficiency has anything to do with these side effects. If the problem were that simple, supplementing DHT (i.e. Andractim) would alleviate the problem in every case, which unfortunately isn’t true.

Even though a few men seem to benefit from supplementing DHT, many have made the experience that increasing androgens by any means (Clomid, TRT, DHT, etc.) makes the symptoms worse.

This clearly indicates that the problem is more complex than simple 5AR2 deficiency and more akin to an active resistance of the body against androgens. Misguided androgen receptor autoregulation mechanisms, which silence the AR signal, is a more likely possibility which must be considered.

3a-Androstanediol Glucuronide (3a-diol-G) is a metabolite of the enzyme 3a-HSD, which is responsible for maintaining androgen homeostasis at the cellular level. Given that 3a-HSD is probably induced by AR gene expression, a lack thereof, due to silencing of the AR signal, would equally lead to low 3a-HSD throughput. This would also result in low 3a-diol-G levels. 3a-HSD additionally plays a central role in the synthesis of key neurosteroids. Hence a downregulation of this important enzyme would better explain “brain fog” and depression rather than low progesterone levels would, which many patients don’t even have.

So let’s stick with the facts and not start potentially damaging treatments based on misleading information. The only way we are going to progress in this issue is by getting science involved and not by making wild claims in the Internet."

A short summary of this idea from other sources.

[191]

The more I think about this the more sense it makes. The idea of gene silencing explains the long term effects of a medication and why we continue having issues. Finasteride is no longer in our bodies. Our bodies would normalise. But the damage is done. The genes silenced. If it were primarily hormonal changing the levels of hormones would help. Only a few have had success with this.

Hormonal issues are certainly secondary as our hormones vary significantly on this forum. TRT may help but again it doesn’t get to the root. The idea of methylation and silencing function can explain everything and with some signs of success I believe it is the best avenue worth exploring. It may not cure us but he might certainly help.

If anyone knows how I can go about trying it please let me know.

Chin up folks.

19

[boston332]

Thanks for the summary, Oscar. Much better than I could have done. I hope Awor’s absence from the forum means he’s doing very well. Will start this tomorrow.

19- If you want to try this it shouldnt be that difficult to get Procaine and the needles you’d need. It isnt a controlled substance.

[Bradwaggoner]

Makes sense from reading that. BTW, I hate finasteride even more now…

[191]

Thanks. My main question is whether i.v is the best way.

[bluejaysfan]

Really hope things continue to improve for you (and then us) with this, Awor.

When you get the chance, looking forward to hear how you’re doing.

[m_81]

@boston332

Will start this tomorrow.

Good luck and keep us posted, boston.

Awor or other knowledgeable people, I understand what happened to us (ARs get hypersensitive and then, when DHT comes back, methylation takes place); but what happens to “normal” people? Their ARs don’t get hypersensitive? or, they do but they don’t methylate?

[boston332]

Awor is telling me injections probably will not work. I want to discuss this further with Shippen and Jacobs. Would like to see if I can understand Dr. Shippens reasoning for the injections considering the half life of Procaine. At this point will be Monday at the earliest before I can speak with him. I may start this anyway tonight just to see what happens.

[tim1911]

@boston332

Awor is telling me injections probably will not work

Wasn’t awor saying injections are tthe only thing that will work, in earlier posts?

[boston332]

No, he states intravenous specifically due to the half life of Procaine.

I just injected 1 cc of Procaine with 1/2 a cc of b12. I’ll continue with it until I cant talk to Shippen on Monday and get his thoughts. I have no problems with trying IV if this doesnt work.

[Y-C]

@boston332

Shippen said “a doctor in Europe” was having success with procaine.

It would be interesting to know who is this doctor, since many of us, including myself are from Europe. Maybe an Anti-aging Doctor?

[tim1911]

@awor

@BadLuck

What do you think of the otc procaine pills that are available on the internet?
Do you have theory how some people do get better on their own?

Procaine by a delivery method other than IV will not work for our purpose. The reason for this is the extremely short half life of only about 40-80 seconds.

As to why some people get better on their own: That’s a good question. For one, enzymes exist which demethylate. JHDM2A for example, demethylates promoter regions of genes which express AR regulatory elements. Secondly, it is also possible to loose small amounts of methylation during a cell replication cycles if enzymes responsible for methylation are not sufficiently active (DNMT1, DNMT2 for example). To be frank, the exact function of epigenetic processes such as methylation is still relatively poorly understood. There is still much that needs to be discovered.

[Bradwaggoner]

From wikipedia:

Demethylating agents are compounds that can inhibit methylation, resulting in the expression of the previously hypermethylated silenced genes (see methylation: methylation and cancer for more detail). Cytidine analogs such as 5-azacytidine (azacitidine) and 5-azadeoxycytidine (decitabine) are the most commonly used demethylating agents . These compounds work by binding to the enzymes that catalyse the methylation reaction, DNA methyltransferases; and titrate out these enzymes [1]. Both compounds have been approved in the treatment of Myelodysplastic syndrome (MDS) by Food and Drug Administration (FDA) in United States. Azacitidine and decitabine are marketed as Vidaza and Dacogen respectively. Azacitidine is the first drug to be approved by FDA for treating MDS and has been given orphan drug status [2][3]. Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells.[4]